Various tissue culture systems will be used to study the mechanisms of particulate metal induced carcinogenesis. A numbe of particulate metal compounds will be tested for their carcinogenic activities in the cell transformation assay and selected metal compounds having different cancer ausing activities will be compared for their uptake, sub-cellular localization and site of cellular action during the early stages of neoplastic transformation. Phagocytosis and distribution of the particulate metals will be studied in intact cells by means of light microscopy, video intensification light microscopy, (video recordings of living cells) electron microscopy and elemental mapping with entergy dispersive x-ray analysis integrated with transmission electron microscopy. Parallel biochemical studies will focus upon isolating and purifying cellular components (i.e. isolated nuclei and nuclear DNA, RNA and protein) to determine molecular metal binding sites. Metal concentrations in isolated cell fractions will be measured by means of x-ray fluorescence while crystalline structure of metal compounds in these fractions will be determined by powder x-ray diffraction. The biochemical and intact cell approach will also be applied to study the effect of inhibitors that disrupt metal induced carcinogenesis or that disrupt specific cellular functions (i.e. colchicine, dansylcadaverine, etc.). Our mechanism studies will also focus upon correlating whether carcinogenic metals cause DNA repair, or induce mutations in mammalian cells. These and other studies will help determine whether metals are initiators and/or promoters of carcinogenesis. There are many advantages for using particulate metal compounds to study the mechanisms of chemical carcinogenesis. These advantages will be applied to help in delineting specifically the mechanisms of metal carcinogenesis but hopefully will provide general principles which may lead to a better understanding of chemical induced cancer in general.